The interaction of sex, height, and QRS duration on the effects of cardiac resynchronization therapy on morbidity and mortality: an individual-patient data meta-analysis

Aims: To explore possible associations that may explain the greater benefit from cardiac resynchronization therapy (CRT) reported amongst women. Methods and results: In an individual-patient data meta-analysis of five randomized controlled trials, all-cause mortality and the composite of all-cause mortality or first hospitalization for heart failure (HF) were compared among 794 women and 2702 men assigned to CRT or a control group. Multivariable analyses were performed to assess the impact of sex, QRS duration, HF aetiology, left ventricular end-diastolic diameter (LVEDD), and height on outcome. Women were shorter, had smaller LVEDD, more often left bundle branch block, and less often ischaemic heart disease, but QRS duration was similar between sexes. Women tended to obtain greater benefit from CRT but sex was not an independent predictor of either outcome. For all-cause mortality, QRS duration was the only independent predictor of CRT benefit. For the composite outcome, height and QRS duration, but not sex, were independent predictors of CRT benefit. Further analysis suggested increasing benefit with increasing QRS duration amongst shorter patients, of whom a great proportion were women. Conclusions: In this individual-patient data meta-analysis, CRT benefit was greater in shorter patients, which may explain reports of enhanced CRT benefit among women. Further analyses are required to determine whether recommendations on the QRS threshold for CRT should be adjusted for height. (ClinicalTrials.gov numbers: NCT00170300, NCT00271154, NCT00251251)

Cytochalasin B-induced membrane vesicles convey angiogenic activity of parental cells

Naturally occurring extracellular vesicles (EVs) play essential roles in intracellular communication and delivery of bioactive molecules. Therefore it has been suggested that EVs could be used for delivery of therapeutics. However, to date the therapeutic application of EVs has been limited by number of factors, including limited yield and full understanding of their biological activities. To address these issues, we analyzed the morphology, molecular composition, fusion capacity and biological activity of Cytochalasin B-induced membrane vesicles (CIMVs). The size of these vesicles was comparable to that of naturally occurring EVs. In addition, we have shown that CIMVs from human SH-SY5Y cells contain elevated levels of VEGF as compared to the parental cells, and stimulate angiogenesis in vitro and in vivo

Enhanced Odor Discrimination and Impaired Olfactory Memory by Spatially Controlled Switch of AMPA Receptors

Genetic perturbations of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) are widely used to dissect molecular mechanisms of sensory coding, learning, and memory. In this study, we investigated the role of Ca(2+)-permeable AMPARs in olfactory behavior. AMPAR modification was obtained by depletion of the GluR-B subunit or expression of unedited GluR-B(Q), both leading to increased Ca(2+) permeability of AMPARs. Mice with this functional AMPAR switch, specifically in forebrain, showed enhanced olfactory discrimination and more rapid learning in a go/no-go operant conditioning task. Olfactory memory, however, was dramatically impaired. GluR-B depletion in forebrain was ectopically variable (“mosaic”) among individuals and strongly correlated with decreased olfactory memory in hippocampus and cortex. Accordingly, memory was rescued by transgenic GluR-B expression restricted to piriform cortex and hippocampus, while enhanced odor discrimination was independent of both GluR-B variability and transgenic GluR-B expression. Thus, correlated differences in behavior and levels of GluR-B expression allowed a mechanistic and spatial dissection of olfactory learning, discrimination, and memory capabilities

Bioinformatics in translational drug discovery

Bioinformatics approaches are becoming ever more essential in translational drug discovery both in academia and within the pharmaceutical industry. Computational exploitation of the increasing volumes of data generated during all phases of drug discovery is enabling key challenges of the process to be addressed. Here, we highlight some of the areas in which bioinformatics resources and methods are being developed to support the drug discovery pipeline. These include the creation of large data warehouses, bioinformatics algorithms to analyse ‘big data’ that identify novel drug targets and/or biomarkers, programs to assess the tractability of targets, and prediction of repositioning opportunities that use licensed drugs to treat additional indications

Sir Abraham Hume, Wormleybury, [Wormley, Hertfordshire], to James Edward Smith

Grateful for Smith's condolences on death of his daughter Sophia [Lady Brownlow (1788-1814), wife of John Cust, 1st Earl Brownlow], a "victim of [...] this cruel winter". Believes the people at Cambridge are "most obstinatley blind to their own interests" [Smith's unsuccessful campaign to become Professor of Botany], comments that the Botanical Garden there last summer was in a "most forlorn uncomfortable state". Wishes Smith knew Mr Eustace, a writer who has been staying at Wormleybury. Sophia's death has "badly checked" the pleasure he gained from his plants and garden, which after the death of his wife Amelia were cultivated solely for Sophia